Lopinavir/ritonavir has been the recommended boosted protease inhibitor for treatment-naive individuals in all guidelines since its approval in the year 2000. More recently, the rest of ritonavir-boosted protease inhibitors (namely lopinavir once-daily, fosamprenavir, saquinavir, atazanavir, and darunavir) have demonstrated non-inferior antiviral efficacy at 48 weeks than lopinavir twice-daily. Overall, all ritonavir-boosted protease inhibitors display a high genetic and pharmacological barrier to resistance development and protect the rest of the drugs on board in the regimen, achieving similar CD4 count gains among them. During the last year, studies conducted with atazanavir and darunavir have demonstrated superior virologic efficacy against lopinavir at 96 weeks in their pivotal trials. These two protease inhibitors provide significant improvements in triglycerides and gastrointestinal toxicity, together with simpler once-daily formulations, compared to lopinavir. In the case of atazanavir, this is mainly driven by a lower rate of discontinuations due to drug-related side effects, as pure antiviral efficacy is essentially similar to lopinavir. Furthermore, the gastrointestinal intolerance of lopinavir is actually compensated by an increased risk of hyperbilirubinemia and jaundice with atazanavir, but this is more a cosmetic problem and rarely a cause of drug withdrawal. Darunavir has been licensed to be taken once-daily in treatment-naive patients, and shows significantly better lipid and gastrointestinal tolerance than lopinavir. Robust sensitivity analysis with darunavir prove superior antiviral efficacy than lopinavir at 96 weeks also when non-virologic failures (toxicity and discontinuations) are censored, or when only patients receiving lopinavir twice-daily are included in the estimation. Moreover, darunavir has shown superior antiviral efficacy than lopinavir, particularly in three situations of particular clinical concern: high baseline viral load, low baseline CD4 counts, and suboptimal drug adherence. Over the last years, the treatment landscape with ritonavir-boosted protease inhibitors as initial HIV therapy has accomplished significant advances, with improved degrees of efficacy, tolerability, and convenience, that should be used to guide treatment choice in first-line antiretroviral therapy.